A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma.

Lessons learnedThe safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma.BackgroundSimtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro.MethodsPatients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed.ResultsIn total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow-up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients.ConclusionThe addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC. The Oncologist 2017;22:243-e8

The impacts of environmental warming on Odonata: a review

Climate change brings with it unprecedented rates of increase in environmental temperature, which will have major consequences for the earth's flora and fauna. The Odonata represent a taxon that has many strong links to this abiotic factor due to its tropical evolutionary history and adaptations to temperate climates. Temperature is known to affect odonate physiology including life-history traits such as developmental rate, phenology and seasonal regulation as well as immune function and the production of pigment for thermoregulation. A range of behaviours are likely to be affected which will, in turn, influence other parts of the aquatic ecosystem, primarily through trophic interactions. Temperature may influence changes in geographical distributions, through a shifting of species' fundamental niches, changes in the distribution of suitable habitat and variation in the dispersal ability of species. Finally, such a rapid change in the environment results in a strong selective pressure towards adaptation to cope and the inevitable loss of some populations and, potentially, species. Where data are lacking for odonates, studies on other invertebrate groups will be considered. Finally, directions for research are suggested, particularly laboratory studies that investigate underlying causes of climate-driven macroecological patterns

Homeschooling and the criticism of school: hybridisms and educational (dis)continuities

Desde os anos 1960, o homeschooling apresenta dinâmicas de crescimento atualizadas nos diagnósticos da crise do capitalismo e dos sistemas educativos. Por ser praticado por famílias próximas do progressismo libertário, do cristianismo conservador ou de outras inspirações axiológicas, a abordagem investigativa presente neste texto pressupôs romper com uma visão unívoca e alheia à sua diversidade e aos diferentes graus de (in)formalidade dos quotidianos educativos de crianças e de jovens que caracterizam este fenómeno educativo. Procura-se captar as especificidades do ensino doméstico (ED) em Portugal e a sua crescente expressão social e educacional e reflete-se sobre os sentidos das aprendizagens que ele encerra. Conclui-se que o ED parece ser contrário aos horizontes formativos da criança segundo o interesse da sociedade, sendo omisso sobre o seu papel na emancipação dos sujeitos. Confrontam-se a escola e o seu modo de funcionamento a partir do racional do ED, à procura de novas epistemologias e de novas linhas de pesquisa.Since the 1960s, homeschooling has shown growth dynamics updated by the diagnosis of the crisis of capitalism and of educational systems. Because it is practiced by families close to libertarian progressivism, conservative Christianity, or other axiological inspirations, this paper’s approach sought to break with a univocal conception alien to its diversity and to the different degrees of (in)formality of the children’s and young people’s educational daily lives inherent to this educational practice. Therefore, this paper seeks to understand the specificities of Portuguese homeschooling and its increasing social and educational expression, and to reflect on the meanings of the learning it entails. Being unclear about its role on the emancipation of the subjects, homeschooling seems to be contrary to the educational horizons of the child according to the interests of the whole society. This paper confronts school and its way of functioning with the homeschooling rationale in order to search for new epistemologies and new lines of research.info:eu-repo/semantics/publishedVersio

Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials

<p>Abstract</p> <p>Background</p> <p>Breast cancer is the most common cancer in women in the U.S. and Western Europe. Amplification of the her-2/neu gene occurs in approximately 25% of invasive ductal carcinomas of the breast. The first HER-2/neu-targeted approach to reach the clinic was trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER-2/neu protein. Trastuzumab therapy prolongs the survival of patients with metastático HER-2/neu-overexpressing breast cancer when combined with chemotherapy and has recently been demonstrated to lead to dramatic improvements in disease-free survival when used in the adjuvant therapy setting in combination with or following chemotherapy. Here, we performed a meta-analysis of completed clinical trials of adjuvant trastuzumab in the adjuvant setting. Survival, recurrence, brain metastases, cardiotoxicity and directions for future research are discussed.</p> <p>Methods</p> <p>A meta-analysis of randomized controlled trials (RCT) was performed comparing adjuvant trastuzumab treatment for HER2-positive early breast cancer (EBC) to observation. The MEDLINE, EMBASE, CANCERLIT and Cochrane Library databases, and abstracts published in the annual proceedings were systematically searched for evidence. Relevant reports were reviewed by two reviewers independently and the references from these reports were searched for additional trials, using guidelines set by QUOROM statement criteria.</p> <p>Results</p> <p>Pooled results from that five randomized trials of adjuvant Trastuzumab showed a significant reduction of mortality (p < 0.00001), recurrence (p < 0.00001), metastases rates (p < 0.00001) and second tumors other than breast cancer (p = 0.007) as compared to no adjuvant Trastuzumab patients. There were more grade III or IV cardiac toxicity after trastuzumab (203/4555 = 4.5%) versus no trastuzumab (86/4562 = 1.8%). The likelihood of cardiac toxicity was 2.45-fold higher (95% CI 1.89 – 3.16) in trastuzumab arms, however that result was associated with heterogeneity. The likelihood of brain metastases was 1.82-fold higher (95% CI 1.16 – 2.85) in patients who received trastuzumab.</p> <p>Conclusion</p> <p>The results from this meta-analysis are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER-2-positive EBC based on the risk: benefit ratio demonstrated in these studies. Adequate assessment of HER-2/neu status is critical, and careful cardiac monitoring is warranted because of cardiac toxicity. Clinical trials should be designed to answer unsolved questions.</p

Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer

Trastuzumab is an effective treatment for patients with metastatic breast cancer (MBC) that overexpresses HER-2. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. A retrospective chart review was conducted of 100 patients commencing trastuzumab for metastatic breast cancer from July 1999 to December 2002, at the Christie Hospital. Seven patients were excluded; five patients developed central nervous system metastases prior to starting trastuzumab, and inadequate data were available for two. Out of the remaining 93 patients, 23 (25%) have developed BM to date. In all, 46 patients have died, and of these 18 (39%) have been diagnosed with BM prior to death. Of the 23 patients developing BM, 18 (78%) were hormone receptor negative and 18 (78%) had visceral disease. Univariate analysis showed a significant association between the development of cerebral disease and both hormone receptor status and the presence of visceral disease. In conclusion, a high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases. HER-2-positive breast cancer may have a predilection for the brain, or trastuzumab therapy may change the disease pattern by prolonging survival. New strategies to address this problem require investigation in this group of patients

Isolated Hypoxic Hepatic Perfusion with Retrograde Outflow in Patients with Irresectable Liver Metastases; A New Simplified Technique in Isolated Hepatic Perfusion

Background: Isolated hepatic perfusion with high-dose chemotherapy is a treatment option for patients with irresectable metastases confined to the liver. Prolonged local control and impact on survival have been claimed. Major drawbacks are magnitude and costs of the procedure. We developed an isolated hypoxic h

Whole brain radiotherapy for brain metastases from breast cancer: estimation of survival using two stratification systems

BACKGROUND: Brain metastases (BM) are the most common form of intracranial cancer. The incidence of BM seems to have increased over the past decade. Recursive partitioning analysis (RPA) of data from three Radiation Therapy Oncology Group (RTOG) trials (1200 patients) has allowed three prognostic groups to be identified. More recently a simplified stratification system that uses the evaluation of three main prognostics factors for radiosurgery in BM was developed. METHODS: To analyze the overall survival rate (OS), prognostic factors affecting outcomes and to estimate the potential improvement in OS for patients with BM from breast cancer, stratified by RPA class and brain metastases score (BS-BM). From January 1996 to December 2004, 174 medical records of patients with diagnosis of BM from breast cancer, who received WBRT were analyzed. The surgery followed by WBRT was used in 15.5% of patients and 84.5% of others patients were submitted at WBRT alone; 108 patients (62.1%) received the fractionation schedule of 30 Gy in 10 fractions. Solitary BM was present in 37.9 % of patients. The prognostic factors evaluated for OS were: age, Karnofsky Performance Status (KPS), number of lesions, localization of lesions, neurosurgery, chemotherapy, absence extracranial disease, RPA class, BS-BM and radiation doses and fractionation. RESULTS: The OS in 1, 2 and 3 years was 33.4 %, 16.7%, and 8.8 %, respectively. The RPA class analysis showed strong relation with OS (p < 0.0001). The median survival time by RPA class in months was: class I 11.7, class II 6.2 and class III 3.0. The significant prognostic factors associated with better OS were: higher KPS (p < 0.0001), neurosurgery (P < 0.0001), single metastases (p = 0.003), BS-BM (p < 0.0001), control primary tumor (p = 0.002) and absence of extracranial metastases (p = 0.001). In multivariate analysis, the factors associated positively with OS were: neurosurgery (p < 0.0001), absence of extracranial metastases (p <0.0001) and RPA class I (p < 0.0001). CONCLUSION: Our data suggests that patients with BM from breast cancer classified as RPA class I may be effectively treated with local resection followed by WBRT, mainly in those patients with single BM, higher KPS and cranial extra disease controlled. RPA class was shown to be the most reliable indicators of survival

CSR, co-optation and resistance: the emergence of new agnostic relations between business and civil society

This article examines the theoretical implications of the changing relationships between NGOs and businesses that have emerged as a response to the evolving agenda around CSR and sustainable development. In particular, it focuses upon examining whether greater engagement from non-governmental organisations (NGOs) in this area reflects a process of appropriation and co-optation of protest by the business community. To examine this process, the article considers two forms of appropriation—appropriation of language and appropriation via participation—as a basis for discussion. While co-optation pressures are identified within both areas, the article argues that co-optation is identified almost as an inevitable outcome of engagement without significant consideration of the ability of movements to identify and respond to these processes. In identifying an alternative approach, the article utilises Mouffe’s framework of agonistic pluralism. Mouffe’s framework, it is argued, provides an understanding of the way in which agonistic relationships are emerging between NGOs and businesses while highlighting the continuance of conflict between parties struggling to influence the contested interpretations of responsible business